Cohorts of Docetaxel or Cabazitaxel in Combination With the Potent CYP3A4 Inhibitor, Clarithromycin

NCT03043989 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: J16144IRB00117591
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical trial is being conducted to recommend a safe and tolerable phase 2 dose of docetaxel or cabazitaxel when combined with clarithromycin in men who have developed castrate-resistant prostate cancer. In the castrate-resistant setting, resistance to taxane therapy inevitably develops. Men who develop resistance to taxanes have a very poor prognosis, and few treatment options. It is believed that CYP enzymes contribute to docetaxel and cabazitaxel resistance in metastatic prostate cancer, and this resistance can be mitigated through pharmacologic CYP inhibition. In this study a potent CYP3A inhibitor, clarithromycin, will be co-administered concurrently with either docetaxel or cabazitaxel, whose systemic metabolism is dependent of CYP3A4, with the intent to overcome resistance to taxanes.

Conditions

Prostate Cancer

Keywords

docetaxel; cabazitaxel; phase 1b; castration-resistant; bone metastasis

Outcome Measures

Primary Outcomes (2)

• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  3 years

• Escalate dose up the maximum tolerated dose achieved, and initiate this as the recommended phase 2 dose of docetaxel and of cabazitaxel when it is combined with clarithromycin.

  3 years

Secondary Outcomes (2)

• Compare docetaxel OR cabazitaxel exposure (maximal [Cmax] when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.

  3 years

• Compare docetaxel OR cabazitaxel exposure ( total [AUC]) when combined with the strong CYP3A4 inhibitor clarithromycin to historic controls.

  3 years

Study Arms (2)

Docetaxel and clarithromycin combination

ACTIVE COMPARATOR

Docetaxel will be administered by intravenous infusion over 1 hour every 3 weeks on day 1 of each (3 week) cycle for a total of 18 weeks. Clarithromycin will be administered orally at 500mg twice a day for 3 days per cycle on days -1, 1, and 2.

Drug: Docetaxel; Drug: Clarithromycin

Cabazitaxel and clarithromycin combination

ACTIVE COMPARATOR

Cabazitaxel will be administered by intravenous infusion over 1 hour every 3 weeks on day 1 of each (3 week) cycle for a total of 18 weeks. Clarithromycin will be administered orally at 500mg twice a day for 3 days per cycle on days -1, 1, and 2.

Drug: Cabazitaxel; Drug: Clarithromycin

Interventions

Docetaxel DRUG

6 infusions of Docetaxel with 18 doses clarithromycin

Docetaxel and clarithromycin combination

Cabazitaxel DRUG

6 infusions of Cabazitaxel with 18 doses clarithromycin

Also known as: JEVTANA

Cabazitaxel and clarithromycin combination

Clarithromycin DRUG

18 doses of clarithromycin with either Docetaxel or Cabazitaxel

Cabazitaxel and clarithromycin combination; Docetaxel and clarithromycin combination

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men with metastatic castrate-resistant prostate cancer (prostate cancer progressing despite castrate levels of testosterone \<50 ng/dL), using standard measures of progression defined by PCWG2
• Have received at least 4 cycles of docetaxel or cabazitaxel, and less than ten, with two consecutive rising PSA values, checked at least 7 days apart. No PSA decline in last 42 day
• Bone disease documented by either: a positive bone scan, CT scan, or MRI; or biopsy-proven bony metastases
• Age ≥18 years
• ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
• Have normal organ and marrow function defined as:
• absolute neutrophil count ≥1,500/mcL
• platelets ≥100,000/mcL
• total bilirubin (within normal institutional limits)
• AST/ALT ≤ 2.5 × ULN (or ≤ 1.5 x ULN in conjunction with alk phos \>2.5 x ULN for Docetaxel
• AST ≤ 1.5 x ULN for Cabazitaxel
• creatinine clearance-no minimum for Docetaxel
• creatinine clearance- ≥ 30 mL/min/1.73 m2 for Cabazitaxel
• No evidence of clinical progression, in the form of increased lesions on cross-sectional imaging, or new cancer-attributable symptoms or worsening of existing symptoms
• Ability to understand and the willingness to sign a written informed consent document

You may not qualify if:

• Patients who have residual toxicities \> Grade 2 attributed to taxane therapy, except for neuropathy, who are excluded if \> grade 1
• Patients who are receiving any other investigational agents or have within the last 28 day.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to clarithromycin or taxanes
• Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Received more than 10 cycles of docetaxel \[for docetaxel cohort only\] or 6 of cabazitaxel \[for cabazitaxel cohort only\]
• Last docetaxel or cabazitaxel dose \> 6 weeks prior to enrollment
• Patients with a documented history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes, or taking drugs that are known to prolong the QT

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Maryland Technology Development Corporation: collaborator

Study Sites (1)

Johns Hopkins Hospital

Baltimore, Maryland, 21231, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Docetaxel; cabazitaxel; Clarithromycin

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Erythromycin; Macrolides; Polyketides; Lactones

Study Officials

• Michael A Carducci, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 26, 2017
• First Posted: February 6, 2017
• Study Start: March 21, 2017
• Primary Completion: July 26, 2019
• Study Completion: July 26, 2019
• Last Updated: February 17, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)